Fundamentals III: Role of Lipoprotein(a) in ASCVD and Investigational Lipid-Lowering Agents

John Giacona: So moving on to fundamentals part 3: role of Lp(a) and ASCVD and investigational lipid lowering agents. I will turn it over to Viet Le.

Viet Le: Great. Thank you everyone. And I'm so proud, I'm so proud of everyone. This is great. So as we get into Lp(a), I've noticed that there are some questions in the chat about these and so let's move forward.

[1:07:07]

Additional Risk Factors That Inform ASCVD Risk

As we think about risk enhancers, so I kind of showed you the INNERHEART study and how lipids really drive, 50% is the attributable risk in terms of events. So these are other things that will help inform whether or not patients are at risk. It contextualizes for us, you know, is this patient someone that we really need to pay more attention to? So here are some of the risk enhancing factors. I won't read through them as they are in the guidelines, both the 2018, 2022 and we'll see if they're included again as guidelines are updated soon.

But Lp(a) is 1 of those things that features large and has been there, but not very many people actually order this. I'll just kind of editorialize right now that we have 8 billion plus people on the earth and less than 1%, or maybe 1%, have had an Lp(a) tested. And so we've got to do better. And I'll show you why.

[1:08:05]

Lp(a) and Residual ASCVD Risk

So as we kind of think through this, what is Lp(a) and why does it add to this risk? Well, you have to think about it as probably the bad brother of LDL cholesterol. They're both ApoB 100 particles. And if you're looking at this graphic here, what you see is a little squiggly, almost like a curly hair—that's something I don't have—around this blue ball of LDL. And that's the ApoB 100 that is kind of keeping this structure together.

But then you see this little tail on the bottom. That is something that LDL cholesterol doesn't have, but both of them share the little curlicue on the outside. That's ApoB 100. Then you have this tail of apolipoprotein (a).

Now who has it, who doesn't? We'll talk about that. But we figure that normal levels are about 30 or less mg/dL. Or if you're doing nanomoles, that's the particle numbers, 75 or less is quote unquote normal, and it will stay normal. If it's in that low range, it will be in the low range. But what we know is that 1 in 5 or about 20% of the population have a high Lp(a). And now, you know, whatever that is, we tend to say, well, it's it stays the same. I will just say that if you have high Lp(a), it's generally high always. It doesn't come down into the moderate or low range at all. But it can vary by 20-30 mg/dL. It doesn't get affected by lifestyle. So yes, please keep doing it, but it doesn't modify by the way we change our diet or exercise.

And where we get the original data is from a subset of patients of 16,000 or more that when they had an Lp(a) tested in tertiles, and that's why we kind of separate these from low, moderate and high risk, those high risk individuals were those individuals with Lp(a) of 50 mg/dL or higher, or 125 nmol or higher, had more events, like a lot more events and early. So I'll hearken back to that figure where you saw cholesterol burden years. If it's high, it's high since birth. So that's why it's so important to recognize these and understand the inherent genetic risk in Lp(a).

[1:10:41]

Lp(a) Testing: Guidance and Challenges

So here's the guidance for testing. This is problematic because I've been a moderator and a chair of several sessions, whether it's ASPC or somewhere else, where we've discussed, should we be doing this? Should we test everyone? I'll tell you my bias: yes. But what does the guidance tell us right now?

Well, you know, here, if you have a family history or a patient with a family history of early, early events—I've kind of answered some questions that have been out there—but less than 55 years of age in a male relative, primary male relative, or less than 65 years of age and a female relative counts as premature. And in those individuals, then probably this genetic risk is there; test for Lp(a). It's in the slide. Great.

And then primary severe hypercholesterolemia. So patients that I see that I'm looking at the LDL cholesterol, there's about a 40% chance in those individuals that they have Lp(a) that's elevated also. And here's kind of the dirty secret is that when we do a lipid profile, mostly that's calculated, right. Total cholesterol, triglycerides. And so that LDL cholesterol number that you're getting is a calculated number. And Lp(a) gets kind of mixed in there and calculated. So if you're at 160 mg/dL, part of that might actually be Lp(a) being counted as LDL cholesterol.

So the presence of an elevated, greater than 50 mg/dL or greater than 125, really increases your risk for cardiovascular disease. And it tells us that perhaps we need to optimize risk better. So although statins don't lower Lp(a), it helps to lower the overall risk of lipoproteins, including LDL cholesterol.

So what are the challenges? Look, you know, it just isn't covered. When you do an Lp(a) test, there's lack of reimbursements. We don't have any treatment options. I'm a clinical trialist in 2 of the 5 trials going on right now, and we just don't know if lowering will lower events. That's why we do clinical trials.

And then often we look at Lp(a) as a risk-enhancing factor. So you identify. Why do you ask about smoking? Why do you ask about family history of events? Why do you check other things? To understand that person's risk and individualize it to the person in front of you.

The good news is that there's free Lp(a) testing. So everyone on this webinar, go to the Family Heart Foundation and/or just, you know, use your local search engine and look up free Lp(a) testing Family Heart Foundation. And there is free testing there for you.

[1:13:35]

Dallas Heart Study: Lp(a) Levels by Race/Ethnicity

So when we look at this by race and ethnicity, you find that it tends to run higher in blacks. And I will tell you that there may be a reason for that, because as we follow the line of where that Lp(a) mutation starts from, it's believed to, and as we kind of look back at inheritance, back from Africa. And we could discuss, you know, the history of why that is, but that's where the genesis of Lp(a) seems to come out from. And then it's, you know, moved out from that point to all points of the globe. So, less so in females and males, white, and also in Hispanic male and females, but certainly more in the black population.

[1:14:23]

Lipoprotein(a) Levels and Risk of Aortic Valve Stenosis

And so then you've probably heard, or maybe not, there's this ASCVD risk, and then there's a risk for aortic valve stenosis. There's something about Lp(a) increases calcification around the aortic valve. And so this is something that we've observed and you can kind of see by on that left hand side the level by mg/dL of Lp(a) and as that goes downwards or meaning, the number goes up in terms of this graph, the risk of aortic valve stenosis increases.

One of our partners or colleagues, Amy Simone, is a structural heart PA and that's something that they've been identifying in TAVR-SAVR is Lp(a) seems to be a little higher in those individuals, and probably by no mistake.

[1:15:16]

Effects of Approved Lipid-Lowering Therapies on Lp(a)

As we look at approved lipid-lowering therapies for Lp(a), big egg, zero. Currently there are there are no FDA-approved therapies for Lp(a), and maybe a little touch of an increase sometimes when people are on statins. That's not a reason to not use statins. We don't know actually what that means when Lp(a) goes up a little bit with a statin being utilized. So please don't create alarm here in this space. But as you look at this, very minimal effects.

PCSK9, as you kind of see under statins, ezetimibe and then the PCSK9s, which include inclisiran—it targets PCSK9—we do see a reduction in Lp(a). And there's some secondary analysis and observational data that suggests that it does further independently reduce MACE events, major adverse cardiovascular events. But it's hypothesis generating. We just think, okay, this is an observation, it might lead you toward PCSK9 sooner in those individuals with LDL cholesterol and elevated Lp(a), but otherwise I wouldn't hang your hat on it. That’s why we do clinical trials.

You see niacin in there? I don't use niacin at all. There's not really any good data for cardiovascular risk reduction. Yes, it might move numbers, but numbers are not the same as events. Okay, so be very careful.

[1:16:46]

Lp(a) Antisense Oligonucleotide Therapy

As we kind of look at the therapies. you know, Laura kind of went through all the different LDL cholesterol therapies and so here as we kind of think of Lp(a) and how do we target this? Well, actually we're moving upstream from the protein itself to interfere with how it's created. So here's 1 way: antisense oligonucleotide therapy. There's this Lp(a) gene and then somehow, if you can interrupt interfere with that transcription to the actual protein, then you don't have to target the protein. You target upstream from it and try to interfere with its development. And in doing so, then you don't create that little tail, that ApoA that sticks onto an ApoB particle.

[1:17:35]

AKCEA-APO(a)-L_Rx: Phase II Study of Effect on Lp(a) Levels

So this is 1 of the seminal trials that that came out for Lp(a) using an antisense oligonucleotide. And here's the phase 2 trial, that led to 1 of the trials that I'm on, Pelacarsen or HORIZONs is the trial and we are using Pelacarsen. You can see in that very far column, it can reduce Lp(a) by up to 80%. Now, is that enough? We don't know. Remember we're looking at LDL cholesterol. We think 50%, right, and so we're not sure if this monotherapy that addresses Lp(a) protein reducing it by 80%—I mean, I hope we see an effect, but we're not sure, especially when you think of just the PCSK9 reducing by up to 30% and seeing an event or effect there. Well, we hope it translates to an effect in these Lp(a)-lowering therapies.

[1:18:36]

Recent and Ongoing Research: Emerging Agents for Lp(a) and Residual Risk Reduction

So here is some recent and ongoing research emerging for Lp(a), but also a little bit for PCSK9. So it's kind of combined. But in this first box you see the Lp(a)-lowering small interfering therapies. The bottom 1 is Pelacarsen. That's an antisense oligonucleotide. So not all of these are siRNAs. But to briefly explain that, small interfering RNA I showed you and I'm going to go back here.

[1:19:06]

Lp(a) Antisense Oligonucleotide Therapy

Here you go. Here's the antisense oligonucleotide. So here that ASO or antisense oligonucleotide also interferes with messenger RNA, but not as effectively as a small interfering RNA. That's a little bit in front. And as you do that, it's a difference of doing once-a-month injections to now 6 months, once every 6 month injection. And you have a type already. It's called inclisiran and that inclisiran affects then that PCSK9 in that same way.

[1:19:41]

Recent and Ongoing Research: Emerging Agents for Lp(a) and Residual Risk Reduction

So you may or may not have known that we already know about a small interfering RNA, but olpasiran is 1 of the therapies or excuse me, I shouldn't say therapy, but it's a drug, and then lepodisiran, and that's the other clinical trial that I'm involved with, ACCLAIM, and then pelacarsen. So those 2 trials there. And it's amazing to see anywhere from 70 up to 95% reduction, almost reducing it to undetectable. So we're hopeful that these will translate to actual reductions in events.

And now the other emerging lipid modifying therapies, in that lighter purple, lerodalcibep is a PCSK9 therapy. And enlicitide, which if you were paying attention to the American Heart Association conference, they just reported out CORALreef, and so look for that to first in class oral PCSK9 therapy that should be available here pretty soon.

And then obicetrapib, I don't think these CETP inhibitors are done, but I thought so, here's obicetrapib, and it not only increases HDL, and I don't think that's the effect, but pretty effective LDL cholesterol lowering therapy as well, somewhere around 40% and also anti-inflammatory, etc. So look for some cool things that will help us support patients in lowering their LDL cholesterol.

[1:21:21]

Updated Global Guidance: Lp(a) Screening and Risk Stratification

So here's the updated guidance. I love that the National Lipid Association just went right to it. They said, look, this is something that we know we can test for that it's genetic and if it's low, it's low. You don't have to test that again. And if it's high, it is a risk enhancing factor and we should address that. So they said everyone 1 time in their life should be tested. And of course it will be multiple times if we have a drug therapy, now we have drugs that are being tested, but if we have a therapy then you're going to test it like we do with LDL cholesterol. But here at least once is the clinical guidance from the National Lipid Association.

Heart UK also has their consensus statement on risk. So someone asked in in the questions what constitutes risk. You can kind of see minor, moderate, high risk. I almost never tell people that they are not at risk. So when the Lp(a) is normal there are other risk factors. I just say Lp(a) is not necessarily driving that risk. Okay, so you just have to be careful in how we talk about this. European Atherosclerosis Society, most everyone is at least in line with 50 mg/dL, or 125 nmol/L, as really the threshold for high risk.

Okay, so what is the implication? Well, early Lp(a) testing enables, at this point, a 1-time assessment of okay, that's not contributing to risk or, yes, that is contributing to a lot of risk and we have to address it as a risk factor.

So I'm going to turn the time back over to John.

[1:23:07]

Skill Building and Feedback III

John Giacona: Thank you so much Viet. So we'll move into our last skill building feedback session. And as always we will go with a patient case.

[1:23:20]

Patient Case 3: Evelyn, 58-Yr-Old Woman

So this is Evelyn, a 58 year old woman. Her chief complaint, she has concerns about family history of early heart disease. Her father died of an MI at 54 years old, and her older brother had coronary stents placed at 52. Despite optimal LDL, her cardiologist ordered advanced testing due to her family history. Her Lp(a) came back markedly elevated at 180 nanomoles per liter. Her current therapy is rosuvastatin plus ezetimibe. Her past medical history includes hypertension, prediabetes, and hyperlipidemia. For lifestyle, she reports healthy diet and exercising regularly, and that she's adherent to therapy. In recent findings, her LDL was 65. Her Lp(a) was at 180, which is elevated, as Viet just pointed out to us, ApoB at 85, hsCRP 1.8, and she had a CAC score of 210.

[1:24:19]

Poll 9

So with this patient in mind, let's move on to our poll. So why does Lp(a) matter in Evelyn's case?

1. It reflects poor adherence to statins
2. It’s a marker of inflammation, not lipids
3. It contributes independently to ASCVD risk through atherogenic, prothrombotic, and inflammatory mechanisms
4. It’s not clinically relevant without elevated LDL-C

Excellent. Thank you all for participating.

[1:25:06]

Let’s Discuss: Translating Risk Into Care

So quick discussion before I bring back Viet and Laura. So in this patient what is happening? So she's having persistent ASCVD risk despite optimal LDL level. Her Lp(a) is conferring lifelong proinflammatory and prothrombotic burden, and as Viet pointed out, there's no currently FDA-approved Lp(a)-specific therapies, but her risk remains actionable. And that is a very important point that when I bring Viet and Laura back, I know they're going to talk about. Right. We still use Lp(a) as a risk enhancing feature and there is action that we can take, right?

So, what to do in this patient case? We need to document her elevated Lp(a) and counsel her on risk implications. We need to optimize other modifiable risk factors. Being a blood pressure specialist, I definitely think that blood pressure is a huge risk factor that we can modify. Making sure that her blood pressure is controlled, that her glucose is controlled, her weight and diet are key factors that we need to focus on. Lifestyle first in everyone. We can consider PCSK9 inhibitor for additional LDL lowering benefit in her. And of course, with every patient, we engage in shared decision making and patient education.

[1:26:27]

Faculty Discussion

And so with that, I want to grab Laura and Viet’s attention to get their insights on how we can frame Lp(a) as an actionable risk factor with our patients.

Laura Ross: Great questions and great discussion. I think framing Lp(a) as being actionable, you know, we don't just not ask patients about their family history. We can't change it if there's a high prevalence of cardiovascular disease, but it does help us know; history likes to repeat itself, let's be more aggressive in treating their cholesterol. If they have high Lp(a), let's be more aggressive and pulling all the levers that we can. The smoking, the lifestyle changes, the blood pressure. And 50% of that population attributable risk is the LDL. So I think that frames the discussion. I talk about Lp(a) as being a sticky cholesterol that seems to stick with patients, so to speak. That's why it sticks on the aortic valve. It likes to stick in the arteries. And so if we can't significantly change it, what can we do to just make sure there isn't as much cholesterol that can cause other problems?

And I think these trials that are coming up are so exciting. I'm subinvestigator on the OCEAN(a) trial. I have a patient list in our electronic medical record of everyone who has high Lp(a) so that even if they don't qualify for the study, I will be ready for when these drugs come out. And I've talked to patients about pelacarsen probably being the first 1 they'll be available to prescribe. And so getting patients excited to know maybe we can't prescribe something right now, but we will in the future.

And I think I have not had trouble getting it covered by insurance. It may be because I'm in Minnesota, if you can't tell from my accent, that if I just submit that National Lipid Association recommendation that it be checked on everybody once, people are pretty quick to cover it if the patient gets stuck trying to get free testing. At the American College of Cardiology meeting, you could stand in line to get your Lp(a) tested for free. So there are ways around this, but I think the cost shouldn't be as much of a barrier because of these resources. How about you Viet?

Viet Le: Yeah, great points and certainly as I said, the Family Heart Foundation does have a free Lp(a) testing as well. And I use this actually extensively for my patients when their Lp(a) is elevated, it doesn't help them but now I've identified a proband, someone that from a genetic standpoint, their siblings have a 50% chance of having an elevated Lp(a). Their children also have a 50% chance of having inherited propensity to high Lp(a). And so, again, it's the easiest way for me to be able to test and get families identified.

But, you know, this particular case is the poster person for Lp(a) as the driver of the risk. You know, they're on high intensity statin, ezetimibe is there, their LDL cholesterol personally is addressed, mostly, you know, at 65 mg/dL. As you know, I like to see it lower, but, if we reverse engineered that, her LDL cholesterol probably was like 130, maybe 140 at max. Nothing that sounded FH but that Lp(a) with now dad, brother, with events in their 50s, there's a genetic driver in this person.

And so it's actionable because again, you know, you might not be able to lower that Lp(a) but it's a risk enhancing factor. Now you know, I really need to make sure this patient is solid on lifestyle, is solid on blood pressure management. If she had diabetes, we would be treating that optimally and pushing, you know, not that you would be like, “Oh no, they don't have any other risk. A1c of 18% is great.” No, you would manage those. But now you know, you have to optimize everything even more so because this person is at a much higher risk, because of that Lp(a). So to me it's a great way for a discussion for the patient. Now they recognize the genetic risk and that they've been exposed. I mean, she's 58. She's been exposed since birth to this really high Lp(a) and so, you know, it helps us to really manage the LDL cholesterol better, manage her blood pressure, manage everything else, because it's comprehensive in terms of her overall risk.

John Giacona: Excellent. So I think we are going to have a lot of Q&A, so I'll move to the to the next poll, do some of the posttest, and then I will invite Laura and Viet back because we will have a good discussion about just some general Q&A that we have. So for now I'll move to the poll.

[1:31:30]

Poll 10

So for poll 10 for our audience, what would you tell Evelyn about her high Lp(a)?

1. It’s genetic and not something we can measure accurately
2. It’s a 1-time, inherited marker that increases cardiovascular risk, even when cholesterol is normal
3. It means you’ll need to stop your statin
4. It will come down with diet changes

Excellent, excellent. Thank you for all staying engaged.

[1:32:19]

Poll 11

So moving to poll 11. So let's take a moment to reflect on what this case brought up for you. What is 1 change you can make to integrate Lp(a) into your lipid management practice?

1. Routinely measure Lp(a) at least once in adult patients
2. Incorporate Lp(a) results into ASCVD risk discussions
3. Counsel patients and families about genetic risk and prevention
4. Stay current on emerging Lp(a)-lowering therapies

Excellent. Thank you all.

[1:33:12]

Take-home Points

So reviewing some take home points before I move to the posttest assessment. So all of these were talked extensively by Viet and Laura, so I'll just make them brief, right.

• LDL control should be personalized. We personalize it by combining statins with nonstatins to hit our goal of less than 55 to 70 for most patients.
• It's add on, not replacement, right? Nonstatins compliment statins for deeper and multi multifaceted LDL-C lowering.
• Lp(a) matters right? We screen once, we manage elevated levels through risk optimization.
• And team based care is of the forefront for all of our patients. I mean we are APPs, right? So we collaborate to improve access, adherence and outcomes.
• And lower for longer, right? We don't want our arteries marinating in high LDL-C so early, sustained LDL-C reduction drives our lasting cardiovascular protection.

And so with those take home points, we'll move to our posttest assessments.

[1:34:14]

Posttest Assessment

Posttest 1

Okay. So coming back to this question, a 63-year-old man with ASCVD is on maximally tolerated rosuvastatin. His LDL-C remains 95. And according to the 2022 ACC Expert Consensus Decision Pathway, what is the most appropriate next step?

1. Add ezetimibe to his current regimen
2. Increase dietary fiber intake and exercise
3. Substitute the statin with bempedoic acid monotherapy
4. Refer to a lipid specialist

Excellent. So looking at pretest 1, about 73% said add ezetimibe to current regimen. That went up to 83%. Excellent, excellent. So the answer is, yes, to add Zetia to his current regimen. So Zetia is first line add on to statin therapy when LDL-C remains above goal in ASCVD patients. So combination therapy is guideline endorsed and to improve outcomes and achieve greater than 50% LDL reduction. So great job, team, doing well.

[1:35:50]

Posttest 2

Posttest number 2, a 59-year-old woman hesitates to start a PCSK9 inhibitor due to high copays. What is the most patient centered next step?

1. Delay therapy until next insurance cycle
2. Discontinue lipid therapy and start high intensity lifestyle changes
3. Refer to care coordinator for medication assistance programs
4. Switch to bempedoic acid and OTC supplements

Excellent. So nearly everyone said refer to care coordinator for medication assistance programs, pretest 1 and posttest. Excellent.

So that is what we recommend. Collaborating with care coordinators or pharmacists can help us secure financial assistance for our patients. This demonstrates interprofessional collaboration and ensures equitable access to these therapies. Fantastic.

[1:37:11]

Posttest 3

So moving to our last posttest after this education, how confident are you in explaining to patients the rationale for adding a nonstatin therapy to their statin regimen as a complementary approach to further reduce cardiovascular risk?

1. Not at all confident
2. Slightly not confident
3. Somewhat confident
4. Confident
5. Very confident

Excellent, excellent. We're moving more into the confident and very confident. Great job, Viet and Laura, this is great.

[1:38:06]

Poll 12

Okay, moving to poll 12. Do you plan to make any changes in your clinical practice based on what you learn in today's program?

1. Yes
2. No.
3. Uncertain.

Excellent. Thank you for participating in that.

[1:38:46]

Poll 13

Our last poll. So please take a moment to enter 1 key change you plan to make in your clinical practice based on this education.

[1:39:08]

Question and Answer Session

So at this point, I think we have plenty of time for a question and answer session. So I'll ask Viet and Laura to come back on the screen. And I believe you guys can see, but we have plenty of questions. So I'll just pick the first and we can work our way through.

So this is a good question. What is the relationship between lipid elevation and perimenopause and menopause in an otherwise healthy female without other risk factors?

Laura Ross: Oh, I can take this one. Vested interest in this question, but feel free to chime in, Viet. So we know as estrogen is leaving the building, it's not usually a light switch that goes off, unless it's surgical menopause. That HDL or that healthy cholesterol protein will come down. That's the protein that scoops cholesterol and brings it out, to get rid of it. And the LDL protein wraps around it where it's made and if levels are high, will pack it into the artery. And the unfair thing about menopause is that HDL comes down, the LDL goes up. And also Lp(a) levels have been shown to go up a little bit after menopause. So not so much that you need to recheck them after menopause, but if they haven't been checked before definitely check it in menopause as well. If it's high, it's going to be high after menopause too. But I think those are the unfortunate things that relate to hormonal changes and why women often develop heart disease about ten years after their male relatives as well. And so if you start to see those changes, what can we do to combat it? You know, with other lifestyle risk factors and/or medical therapy as well.

Viet Le: Yeah. A great breakdown. I mean that's exactly, or part of anyways, a big part of why we see that ten-year difference right, between men and women in terms of events. And I will posit here that there are a lot of things in women that we don't understand, not just because I'm a guy, but we just don't understand from a medical standpoint because we don't enroll enough women in clinical trials and so we just assume that they will respond the same way to therapies. And that's just, we don't know.

But from an Lp(a) standpoint, it also can go fluctuate during pregnancy. And so it's 1 of those things that we have to be careful of when, the timing of when we order Lp(a). But I don't know that it's enough to, to make us, you know, too crazy about it. But yeah, this is an area that look for it, we're going to do more and more in this space to understand women in that perimenopause and post-menopause state.

Laura Ross: Well, and this might be an opportunity to say patients who have a history of pre-eclampsia, especially if they were hospitalized with high blood pressure, this hotbed of inflammation and hormonal changes, that's a risk enhancing factor for heart disease. So I've had several patients who have no risk factors. I hear they have pre-eclampsia. Their cholesterol is kind of borderline. I check a calcium score and it's like over 100. No other risk factors. So be asking your patients about that as well.

John Giacona: Excellent. So there are I think 2 separate questions but I'm going to combine them into 1 because 1, it's a very fun question that I know every lipid specialist likes to be asked. And so essentially how low is too low for LDL? And is there a level at which bleeding risk increases?

Viet Le: So I'll start us off on this. And you know, again, I'll reiterate that normal physiology is 20-40 mg/dL. But I think you need to understand LDL cholesterol is just kind of the last end of the station in terms of what apolipoprotein B-100 proteins do. You know VLDL, you know IDL, you know LDL, they're just all different shapes of ApoB 100 particle. You have to understand what they hold. They hold cholesterol esters and triglycerides. And that's what we use, the LDL cholesterol, go to Gemini, go to ChatGPT, and it will say we need LDL cholesterol. That's not true. What you need is cholesterol, which is – LDL cholesterol does not cross the blood brain barrier. It just doesn't. But cholesterol esters and triglycerides do. And it gets unpackaged from VLDL down to LDL cholesterol. So whether you have detectable or not detectable LDL cholesterol matters not in hemorrhage risk. We have not seen it in the clinical trials. And I think the most important trials are the PCSK9 inhibitor trials because of how low folks were finally able to get their LDL cholesterol. But I will say here that how we got to PCSK9 as a drug was based off of loss of function variants, where these patients did not have any PCSK9 and their LDL cholesterols were undetectable. They didn't have brain bleeds, they had no events, cardiovascular events. And so, here I have multiple patients that are less than 10 and in the undetectable range, no brain bleeds at all. That was based on some observational data that's a little bit flawed. So, no to the first. How low is too low? It looks linear. And it continues in terms of reduction in events. And then in terms of brain bleeds, we have not seen this meteoric rise in patients in this PCSK9 era.

Laura Ross: Those are great points, Viet. And I would add, I've gotten a few notes from neurology that have said, well, this patient just had a stroke, can we back off on the cholesterol medication? And that brings me back to the point of treating cholesterol is really important over years and decades. That if they are pregnant, if they just had a stroke, if there's, you know, other things going on, it's reasonable to back off or hold, you know, for a time until that danger zone has kind of passed. But all really good points.

Viet Le: Yeah. And I'll just say 1 more thing in terms of neurology and strokes, remember that it is a class 1 for ischemic strokes to be on a statin. And also that is cardiovascular disease, and that is included in the guidelines to lower LDL cholesterol. It's different if it's a hemorrhagic stroke, of course, and whatever the bleed etiology or cause was. But yeah. So there you have it.

John Giacona: Excellent. So next question I'd like to ask you guys. So if we document aortic stenosis, do you think it would increase the likelihood of insurance companies covering the cost of the Lp(a) test?

Viet Le: I'll leave that to Laura.

Laura Ross: Yeah. I don't think I've tried that. I just have had such success with the free testing and then just ordering it and then following up on the back end. There is a patient who it was denied and then they submitted that they had aortic sclerosis and stenosis. And I don't know which piece of the 100 papers I submitted to them was my “right back at ya” that that got it approved, but I don't think it would hurt. I think that's a really good idea if you're trying to gather the evidence and why this patient is high risk.

Viet Le: Yeah. And from a clinical standpoint, just remember that we're almost kind of cart horse. We're not quite sure where it should be because we know there's an association, it's just, you know, it's not fully clear where that association is. And if we treat Lp(a), if that reduces or prevents aortic valve stenosis or sclerosis from occurring. So. But I think in this case, when they're saying no 80% of the time, regardless of whether there's an indication, then it makes sense to add that in and see if that moves the chain 1 way or the other to approve a therapy that the patient already needs.

John Giacona: Okay. Thank you guys. So another question, and this actually I think it's a really good question because as our population is, you know, we're preserving life and preserving health, people are getting older and even in the blood pressure space, there was a big trial that just came out looking at deprescribing in older patients. And so this question specifically says dealing with several elderly patients, at what point do you think it is safe to come off anti-lipid therapy?

Laura Ross: I think this really comes into play, shared decision making, right. So if I have an elderly patient who has a terminal illness, like, you have bigger fish to fry, let's simplify things. If someone's having a side effect, that's a totally different story where we'll start to back off on therapy, whether it's cutting the dose in half or holding it all together. But the biggest cause of mortality in patients over 65 is cardiovascular disease. So I just am very plain with that and say this is your goal, is to prevent a stroke and heart attack. And to be honest, many say I don't care about heart attack. You get a stent and go home the next day. But a stroke I absolutely don't want. That's just an opportunity to say, well, this is 1 way we can try to help lower that risk for you. And if the cost is a burden, you know, that's another piece of trying to deprescribe. But I think especially in secondary prevention, those patients have a 40% risk of another ASCVD event, that we shouldn't deprescribe just because they're old. You know, I think that's doing them a disservice. What are your thoughts Viet?

Viet Le: Yeah, I think that you're spot on. But there's 2 clinical principles that I tend to follow and age is really not 1 of them. It's frailty, and we can have frail patients at 30, 40, 50, 60 years of age, just as much as we can at 70, 80 and 90. So it's frailty and it's patient goals of what they want moving forward. So that's the first principle.

And the second principle is we have data on what happens when patients are on statins and you stop them. So there's a great Spanish population and French population, they've done this because they have universal healthcare, and they're looking at resources and bandwidth and what's appropriate, etc.. So when you look at patients who have been prescribed statins and at age 75, you stop them in half of those patients and you keep them on the other, guess what? Events start occurring in the first year in the patients that go off of statins. And by the time you get to 5 years, remember now they're 80, there's still a protection in those that remained on statins from 75 to 80 compared to those that go off of statins.

So again, we know that there's benefit That's already the first principle. The second – it doesn't matter what age, by the way – and the second principle is how frail is the patient in front of you? Are you assessing that? And if they are frail, if they're hospice, if they have terminal cancer, if this is a person that the cardiovascular component is not the first thing you're thinking about, then yeah. Deprescribe. Deprescribe. I have this conversation all the time. And I've had unfortunately or fortunately for these patients over the last year, several that have gone to hospice. And we have that conversation, actually, at the time that I start the statin or you know, each year as we kind of talk about our goals of life and health, I bring this up and that's the first thing that we discuss. What medications can I just get rid of here for you to keep you comfortable?

John Giacona: Thank you, Viet, for that. I want to segue right into another sort of question in the chat, because you just mentioned goals. What are some good phrases? I'm assuming this person is asking you guys how you how you approach it. What are some good phrases to ask what their goals are? And I think as a side note, they have ASCVD. And then the question is what are some good phrases to ask what the patient's goals are?

Laura Ross: Great question. I think asking, you know, what are their biggest concerns in the next 5 years and the next ten years? That's where sometimes you'll find out, like, “Oh, I'm a caretaker for my ill partner. I'm worried about money. I'm worried about this or that, or I'm scared to death of having a stroke or, you know, going on dialysis” or those sorts of things, and say, well, here are some levers we can pull to make that less likely. And making those smart goals, which is an acronym for, you know, making it measurable, making it actionable, labeling. What is that thing or 2 that we're going to do between now and your next visit, before we repeat labs again, time-bound. So not like “See you next year. Do these ten things and come on back.” But “What are some actions we can take for that concern today?” can be really powerful.

Viet Le: Yeah, I mean, I come back to this, many of the patients that I receive as a referral from other colleagues don't actually know what their risk is. It's amazing to me to receive a patient who has had bypass and redo and then multiple stents, and when I discuss, I start with, “Let me just tell you what I know.” And I go through that and they're like, what? They did what? I had bypass what? And then I say, well, yeah, that's what happened. And the credibility starts because they're like, oh my gosh, you like know everything about what's happened to me. And so your risk is kind of high to have this again. Like we're doing the same things over and over. It's called insanity when you know we're not fixing anything. So tell me what you want. I mean, this is your risk. This is where you're at. This is what's happened.

They bring the questions. Well, how do I address this? I said, well, let's talk about LDL because that's 1 of the things. And then, you know, you have diabetes, or you have this. And that leads to them asking and being curious about how do I reduce this risk, rather than me forcing therapy on them. I'm just here to tell you where your risk is and where you're heading. Like there's a mountain, you're flying this plane, you're going to hit it, man. You got to pull up, you know. Or they're like, well, how do I pull up the joystick? Do I move it? What?

And so I guide them and that's the single most helpful thing is making sure that the patient understands what their disease is and what the risk is. Then there's no phrases that I need to add after that, they guide the conversation quite readily.

Laura Ross: Great points Viet. I don't think anyone gets excited about LDL numbers. It's probably you and I and probably many on the call like, oh my gosh, that LDL is awful. Patients like, I don't feel awful. What are you talking about? But 1 of my favorite stories is a patient who was smoking. And every year I tell her, like I said before, I recommend that you quit to lower your risk of cancer and heart disease and all of this. And then she quit, and the next time I saw her was like, way to go, Laura. You did it. And she's like, no, no, it wasn't you. I went out with my family and I saw the grandparents who were scrambling up after their kids on a hiking trail, and those who were sitting on oxygen in a motorized wheelchair. And I said, I want to be scrambling after my kids on the path, on my own. And so that was her why. So really trying to find out what is the patient's why, what do they like to do for fun? How can we help you get there? And not just tomorrow, but 5 and 10 years. So, a great question though.

John Giacona: It's such a nice patient story. In blood pressure it's the same. It's, oh I helped them lower their risk or their sodium intake. And it not at all was, it was not me. So, a segue to the next question. So in this question, it says what to do if you have tried several statins with muscle pains and PCSK9 with a rash and severe muscle pain. What would really be the next step as my patient is fearful of trying anything else?

Laura Ross: I think that person would be a great candidate for a drug like inclisiran. Not detectable after 48 hours, but putting that cell machinery to sleep as a small interfering RNA molecule helps you have the effect for 6 months. And so telling them you'll walk through with them. They don't have to stay in the clinic after they have an injection, but they can if they're worried about it. The drug doesn't need to be refrigerated, but it does need to be given by a healthcare professional. So some patients feel good about that too, that they can just get the injection by a nurse. They don't have to do anything. And then tell them, hey, if your hair turns purple, I'd say I've never heard of that. But for you, maybe that's a side effect. We'll stop it and we'll go on to the next, you know, the next therapy, like bempedoic acid or, you know, whatever the next therapy might be. So I think letting them know you're on their side. The side effect isn't reported very often, but anything's possible. So I'm here to listen to you if that occurs.

And just because I'm talking about inclisiran and I saw 1 more question in the chat about that HealthWell grant, that is just for Medicare patients. And it works really great for people who have Medicare and supplemental to cover inclisiran pretty much 100%. I have many patients who don't pay anything for it. So that was another piece of information on how to make it easier for patients. Because we give the medication in the clinic, it comes out of their drug benefit, not out of their prescription benefit. So for all these reasons, that might be a good option for that patient. Viet, any tips on that question for you?

Viet Le: Yeah. I mean, I think, again, part of that question is sorted into like drug effect and it's an appropriate question. We run into it all the time. What I bring them back to is again, your risk, your disease, and then how we treat those things. And typically then they're like okay, so there's only these set of drugs that are available that address this thing and this is where the data is. Yes. And I talk mechanism all the time. I don't know if you can see it above me, there’s a whiteboard in my office, but I have a whiteboard in every single clinic room and I actually draw mechanism of action for patients. And I'm very open and transparent about what we do know and what we don't know about certain drugs. In this case, statins, we know that there are mechanisms for why you get myalgias and you don't have to get them on all of them. And then, you know, there's a question about alternative regimens. Can you take a half dose? Can you take it every other day, every other week? I'm like, lick the pill, I don't care. I just want a little bit of that pleiotropic statin effect inside. And then we can lower LDL through other means.

And it's hard, you know, sometimes we just abandon the statin and, fine. We talk about ezetimibe and its mechanism. There shouldn't be myalgias with that. We talk about PCSK9 and here you pose that maybe they had a rash. Yeah. I mean, you know, you kind of jab and do this, you'll have a local site reaction. And that's what we saw in the trial and that's what we've seen ten years after with utilization of it. Evolocumab in particular does have a little bit of latex and so maybe, you know, that's what they're reacting to. I've switched to alirocumab, praluent, and had great success. But Leqvio is fantastic. Inclisiran is fantastic in those patients because there is nothing to have a reaction other than an ouchy.

But there's a second question that kind of came after that is, it's undetectable in 48 hours. The drug itself is undetectable in 48 hours. But yes, the mechanism is such that you'll see the optimal effect for 6 months. And by the way, it's not just 6 months and then suddenly you have PCSK9 activated again. By 12 months, people still have an average 20 to 30% reduction in their LDL cholesterol, almost like taking ezetimibe daily for 365 days to reduce their LDL cholesterol. And that's a mechanism, you've put to sleep that messenger RNA. There's no systemic effect for that. There just isn't. And so that's why inclisiran is such a fantastic medication. I challenge you to look at the FDA insert. There's whole sections, 3, 5, 10, 17. They're missing because there weren't any side effects reported, that were any more than placebo, by the way.

So, yeah, this is tough. But I come back to risk, disease, what are your goals? And often then patients readjust and go, okay, I'm not just saying no meds. I'm saying I really have a goal to have less events. So maybe I am okay with trying some things, that are, you know, evidence based and these are the therapies that are out there. And really through that, I'm cognizant that I have 60 minutes to do a consult. Most of you are like ten, 15 minutes, tops to talk to patients. But I have that that luxury and boy, it's a great way to discuss this with patients.